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. 2025 Aug 1;26(1):49.
doi: 10.1186/s12868-025-00966-4.

Effects of subanesthetic dose of ketamine on motor and cognitive outcomes of harmaline-induced essential tremor model: a focus on Lingo-1 and inflammatory pathways

Mehran Ilaghi #  1 , Zeynab Pirmoradi #  2 , Zahra Esmaili  1   3 , Shamim Hosseinalipour  4 , Leili Rouhi  5 , Adel Soltanizadeh  6 , Mohsen Nakhaie  7 , Kiana Sharififar  8 , Moazamehosadat Razavinasab  9   10 , Mohammad Shabani  11
Affiliations

Effects of subanesthetic dose of ketamine on motor and cognitive outcomes of harmaline-induced essential tremor model: a focus on Lingo-1 and inflammatory pathways

Mehran Ilaghi et al. BMC Neurosci. .

Abstract

Introduction: Essential tremor (ET) is a common neurodegenerative disorder characterized by action tremors and various non-motor symptoms. This study investigated the potential therapeutic effects of ketamine, an NMDA receptor antagonist with known GABA modulatory and anti-inflammatory properties, in a harmaline-induced model of ET in mice. We also evaluated the changes in expression of inflammatory interleukin 6 (IL-6) as well as Leucine rich repeat and Immunoglobin-like domain-containing protein 1 (Lingo-1), a prominent gene involved in the pathogenesis of ET.

Methods: Male Swiss Webster mice were divided into four groups: control, harmaline (10 mg/kg), ketamine (8 mg/kg), and harmaline + ketamine. Tremor severity, muscle strength, locomotor activity, anxiety-like behavior, and passive avoidance learning were assessed. Cerebellar expression of Lingo-1 and IL-6 was analyzed using real-time PCR.

Results: Ketamine did not significantly reduce harmaline-induced tremors but improved muscle strength deficits in the wire grip test. In the open field test, ketamine normalized some harmaline-induced changes in locomotor activity and grooming behavior. No significant differences were observed in passive avoidance learning across groups. At the molecular level, ketamine did not mitigate the harmaline-induced increase in IL-6 expression, and Lingo-1 expression was not significantly altered by either harmaline or ketamine treatment.

Conclusion: Our findings suggest that ketamine has limited efficacy in the harmaline ET model, showing some improvements in motor function and anxiety-like behavior but failing to address core tremor symptoms or modulate inflammatory and Lingo-1 pathways. These results highlight the complex nature of ET pathophysiology and the need for further research into targeted therapeutic approaches.

Keywords: Essential tremor; Harmaline. Lingo-1; Inflammation; Ketamine.

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Conflict of interest statement

Declarations. Ethics approval: All experiments were done in accordance with the ARRIVE guidelines and National Institutes of Health Guide for the Care and Use of Laboratory Animals) NIH Publication No. 80–23, revised 1996). All experiments were performed in accordance with the protocols approved by Kerman University of Medical Sciences Laboratory Animal Care and was accepted by the Institutional Review Board (IRB) of Kerman University of Medical Sciences (IRB code: IR.KMU.REC.1401.017). Consent for publication: Not applicable. Conflict of interest: The authors declare that no conflict of interest in present. The research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Fig. 1
Fig. 1
Experimental timeline and treatment groups. The study consisted of four groups (n = 8/group): Control (saline), Harmaline, Ketamine (8 mg/kg), and Harmaline + Ketamine combination. Tremor was assessed on days 1, 3, and 5. Behavioral tests were conducted on days 5–6, followed by molecular analyses on day 7
Fig. 2
Fig. 2
Effect of ketamine on harmaline-induced tremor severity. Tremor scores were evaluated on days 1, 3, and 5 of the experiment in four groups (n = 8/group): Control (Cont), Ketamine (Ket), Harmaline (Harm), and Harmaline + Ketamine combination (Harm + Ket). Data presented as mean ± SEM. ****P < 0.0001 according two-way ANOVA
Fig. 3
Fig. 3
Effects of ketamine on muscle strength in harmaline-treated mice as measured by wire grip test. The latency to fall (in seconds) was assessed in four groups (n = 8/group): Control (Cont), Ketamine (Ket), Harmaline (Harm), and Harmaline + Ketamine combination (Harm + Ket). Data presented as mean ± SEM. *P < 0.05 according to one-way ANOVA followed by Tukey’s post-hoc test
Fig. 4
Fig. 4
Effects of ketamine on open field test parameters in harmaline-treated mice. Tests performed in four groups (n = 8/group): Control (Cont), Ketamine (Ket), Harmaline (Harm), and Harmaline + Ketamine combination (Harm + Ket). A Number of rearing episodes, B Number of grooming episodes, C Total distance moved (TDM, cm), D Mobility duration (s), E Velocity (cm/s), F Time spent in peripheral zone (s), and G Movement trajectory plots. Data presented as mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001 according to one-way ANOVA followed by Tukey’s post-hoc test
Fig. 5
Fig. 5
Effects of ketamine and harmaline on passive avoidance learning and memory. Tests performed in four groups (n = 8/group): Control (Cont), Ketamine (Ket), Harmaline (Harm), and Harmaline + Ketamine combination (Harm + Ket). A Number of shocks received during training session, and B Step-through latency (s) measured during memory test 24 h after training. Data presented as mean ± SEM. No significant differences were observed between groups according to one-way ANOVA
Fig. 6
Fig. 6
Effects of ketamine and harmaline on cerebellar IL-6 gene expression. Real-time PCR analysis performed on cerebellar tissue collected on day 7 in four groups (n = 4/group): Control (Cont), Ketamine (Ket), Harmaline (Harm), and Harmaline + Ketamine combination (Harm + Ket). Data presented as mean ± SEM. *P < 0.05 according to one-way ANOVA followed by Tukey’s post-hoc test
Fig. 7
Fig. 7
Effects of ketamine and harmaline on cerebellar Lingo-1 gene expression. Real-time PCR analysis performed on cerebellar tissue collected on day 7 in four groups (n = 4/group): Control (Cont), Ketamine (Ket), Harmaline (Harm), and Harmaline + Ketamine combination (Harm + Ket). No statistically significant differences were observed between groups according to one-way ANOVA
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